Excitement Building for PARP Inhibitors in BRCA-Mutated Breast Cancer

The FDA’s recent approval of the first PARP inhibitor, coupled with current research, suggests that this new class of targeted therapy has great potential to help not only patients with ovarian cancer for whom the agent is indicated but also individuals with breast cancer, according to Mark E. Robson, MD, clinic director of the Clinical Genetics Service at Memorial Sloan Kettering Cancer Center.

“It is an exciting time. We have an approval for olaparib (Lynparza) in ovarian cancer and there are active phase III studies for olaparib and other PARP inhibitors in metastatic breast cancer for patients with BRCA1/2 mutations,” said Robson (Table). He is scheduled to provide an update on PARPs in breast cancer at the Miami Breast Cancer Conference during the Medical Oncology track.

Robson is leading the phase III OlympiAD trial that is evaluating olaparib in patients with metastatic breast cancer with germline BRCA1/2 mutations.1 The trial, which is seeking to recruit 310 participants, is open to men and women. Patients will be randomized to receive either olaparib at 300 mg twice daily or physician’s choice chemotherapy of either capecitabine (2500 mg/m2 for 14 days, then repeated every 21 days), vinorelbine (30 mg/m2 on days 1 and 8, then repeated every 21 days), or eribulin (1.4 mg/m2 days 1 and 8, then repeated every 21 days).

PARP inhibitors capitalize on the Achilles’ heel of BRCA1/2-mutated cells whose DNA repair mechanisms are already impaired. Researchers know that the action of a PARP (poly ADP-ribose polymerase) inhibitor serves to fully disable the tumor cell’s ability to repair its damaged DNA, leading to what is known as synthetic lethality, while normal cells suffer little-to-no effect on their ability to survive.

Enough has been accomplished in trials to signal that PARP inhibitors have acquired credibility and traction in breast cancer, Robson said. “I think the message out there is one of cautious optimism,” he said in an interview in advance of his presentation.

In December, the FDA approved olaparib as monotherapy for the treatment of patients with germline BRCA-mutated advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. The indication calls for patients to be tested with an FDA-approved test, and the agency gave its nod the BRACAnalysis CDx as the companion diagnostic.

Nevertheless, it remains unclear whether a positive test for BRCA1/2 mutations can lead to a reliable determination about which patients will benefit from PARP inhibitor therapy, Robson said.

“The technological ability to detect sequence variations in BRCA1/2 is not trivial, but certainly well within the tech- nological capabilities of a number of different laboratories,” Robson said. “Assigning meaning to different variations is a little bit more complicated because certainly protein truncating mutations are relatively straightforward, but other types of sequence variations can be a little bit more difficult to determine whether or not they are likely associated with response.”

In part, it comes down to generating a sufficient evidence base that regulators agree can set the boundaries for those types of determinations, Robson said.

“The FDA and others are certainly trying to figure out what the rules of engagement are here–what’s the right level of regulation so that the clinician can be comfortable that the result he or she has obtained will indeed be tied to an increased likelihood of response,” said Robson. “That’s a tough conversation.”

Many Questions Unanswered

Knowing who will and will not respond to PARP inhibitors and better understanding the mechanisms of resistance are among the crucial questions in ongoing research, as is knowing what other gene mutations might signal efficacy in the use of this class of therapy, Robson said.

“PALB2 is the next most obvious target, but it is going to be more challenging because those mutations are probably tenfold less common than BRCA mutations, and so getting enough patients together to show PARP inhibitors work in PALB2 carriers is going to be very challenging,” Robson said. “It is going to require a lot of collaboration and a lot of effort.”

Researchers believe that up to 10% of breast cancers may be caused by inherited mutations in breast cancer susceptibility genes, including BRCA1/2 and PALB2.2 Mutations in either BRCA gene are associated with a 50% to 80% elevated lifetime risk of developing breast cancer.2 For female carriers of the PALB2 mutation, the risk of developing breast cancer has been estimated at 14% by age 50 years and 35% by 70 years of age.3